Synthesis of Cyclohexapeptides Containing Pro and Aib Residues

Abstract

Cyclization reactions on hexapeptides containing several alpha-aminoisobutyric acid (= 2-amino-2-methylpropanoic acid; Aib) residues and the turn-promoting glycine (Gly) and proline (Pro) residues were investigated. Eight linear hexapeptides were synthesized, and their cyclization was attempted with various coupling reagents. The macrolactamization step proved to be difficult since only three hexapeptides could be cyclized. Two of these latter peptides were the linear precursors of the same cyclic hexapeptide, cyclo(Aib-Aib-Phe-Pro-Aib-Gly) (1). Surprisingly, they gave 1 in almost the same yield. Thus, 1 was obtained in 35% yield upon ring closure at the Phe/Pro site by using DEPBT as the coupling reagent, whereas the cyclization at the Aib/Phe site led to 1 in 28 and 34% yield by using PyAOP and DEPC, respectively (DEPBT = 3-[(diethoxyphosphoryl)oxy]-1,2,3-benzotriazin-4(3H)-one, PyAOP = (1H-7-azabenzotriazol-1-yloxy)tripyrroli-din-1-ylphosphonium hexafluorophosphate, DEPC = diethyl phosphorocyanidate). Another cyclic hexapeptide, cyclo(Aib-Aib-Gly-Aib-Pro-Gly) (2) was prepared in 34% yield when DEPC was used in the cyclization step. The solid-state conformation of 1 was established by X-ray crystallography. 2 Cyclization reactions on hexapeptides containing several Aib residues and the turn promoting Gly and Pro residues were investigated. Eight linear hexapeptides were synthesized and their cyclization was attempted using various coupling reagents. The macrolactamization step proved to be difficult since only three of these hexapeptides could be cyclized. Two of these peptides were the linear precursors of the same cyclic hexapeptide, cyclo(Pro-Aib-Gly-Aib-AibPhe) (1). Surprisingly, they gave 1 in almost the same yield. Thus, 1 was obtained in 35% yield upon ring closure at the Phe/Pro site using DEPBT as the coupling reagent, whereas the cyclization at the Aib/Phe site led to 1 in 28 and 34% yield by using PyAOP and DEPC, respectively. Another cyclic hexapeptide, cyclo(GlyAib-Pro-Gly-Aib-Aib) (2) was prepared in 34% yield when DEPC was used in the cyclization step. The solid-state conformation of 1 was established by X-ray crystallography.3

Synthetic Studies on Stevastelins. 1. Total Synthesis of Stevastelins B and B3

“…With the exception of epoxy peptide 29 , which was subjected to macrolactonization reaction conditions, following Yamaguchi methodology, the other precursors ( 34 , 41 , and 48 ) were exposed, under high dilution conditions, to a variety of coupling reagents, including diethyl cyanophosphonate (DEPC), diphenyl phosphoryl azide (DPPA), O- (7-azabenzotriazol-1-yl)- N , N , N ‘ , N ‘ -tetramethyluronium hexafluorophosphate/1-hydroxybenzotriazole (HATU/HOBt), O- (benzotriazol-1-yl)- N , N , N ‘ , N ‘ -tetramethyluronium hexafluorophosphate/HOBt (HBTU/HOBt), EDCI/HOBt, and pentafluorophenol/EDCI (PFP/EDCI), in different solvents (DCM, THF, DMF, MeCN). The results from these studies revealed that, whereas the macrolactonization did not work at all for compound 29 , resulting in a complex mixture of decomposition products, the macrolactamizations provided more positive results, especially with the epoxy peptide 34 , which afforded the best yields for the desired macrocycle 8 when it was treated with DPPA or DEPC as coupling reagents and DMF as solvent. The epoxy peptide that was obtained represents an interesting compound for the preparation of the 2,3-epoxy analogue of stevastelin B, as well as representing the direct precursor for the natural compound.…”

Synthesis and conformational analysis of 18-membered Aib-containing cyclohexapeptides

“…One of the molecules forms a β-turn with a Aib 4 →Gly 1 hydrogen bond, whereas the other molecule is characterized by a γturn (NH(Aib 4 )→CO(Pro 3 ) hydrogen bond) and an α-turn (NH(Phe 5 )-CO(Gly 1 ) hydrogen bond). In both molecules, Aib4 shows φ,ψ values that belong to the nonhelical conformational space.As a part of our investigation of the synthesis of cyclic hexapeptides containingAib residues,6,22 we have been interested in the conformations of these cyclic molecules in order to estimate if the incorporation of several Aib residues into cyclic hexapeptide structures stabilizes certain types of turns. Previously, we have investigated the cyclization and conformation of hexapeptides containing two or three Aib residues, and two Gly residues in positions 1 and 4 of the peptide backbone 6.…”

Exploiting the MeDbz Linker To Generate Protected or Unprotected C‐Terminally Modified Peptides

“…33 Peptides 13 and 14 were evaluated to determine whether more cyclization-prone substrates could be efficiently functionalized (Table 4). The proclivity of these peptides towards macrocyclization was validated by control reactions with MeOH/Hünig’s base and Hünig’s base alone (entry 2,3,5,6).…”